This invention relates to a method for administering interleukin-2, and to controlled release polymer matrices containing interleukin-2 for use in that method.
The prognosis for patients suffering from malignant tumors of the brain, particularly glioblastoma multiforme, is poor. Conventional treatment regimens include surgical resection, prolonged chemotherapy, and high-dose radiation therapy. Complete surgical removal of these malignancies is difficult at best; and surgery, chemotherapy, and irradiation generally only treat, rather than cure, the condition. The primary result of such therapy is to increase the life expectancy of patients and to improve their quality of life. See W. Shapiro, Treatment of Neuroectodermal Brain Tumors, Annals of Neurology 12: 231-37 (1982).
It is known that very small tumors (approximately 1.times.10.sup.5 cells, or 0.0001 gm) can be suppressed and eventually killed by the immune system. There has been considerable interest in enhancing or supplementing the body's own immunological defense mechanisms as an adjunct to more conventional irradiation and chemotherapy treatment for cancer patients.
One of the most promising immunotherapeutic agents is interleukin-2 (IL-2). IL-2 supports the growth of human cytotoxic T-cells and natural killer cells, and is the essential factor required for the induction and growth of human lymphokine-activated killer (LAK) cells. It is well established that LAK cells may be prepared by culturing IL-2 with peripheral blood lymphocytes. LAK cells have been shown to lyse several types of glial and non-glial tumors, including glioblastoma multiforme. See S. K. Jacobs, et al., In vitro Killing of Human Glioblastoma By Interleukin-2-Activated Autologous Lymphocytes, J. Neurosurg. 64: 114-117 (1986).
Unfortunately, the in vivo administration of IL-2 has been associated with dose-limiting toxicity, including fever, chills, malaise, arthralgias, mylagias, and weight gain related to fluid retention. See M. T. Lotze, et al., In vivo Administration of Purified Human Interleukin-2, J. Immunology 135: 2865-2875 (1985). Despite the in vitro efficacy of IL-2 and LAKs in destroying malignant tissue, in vivo results have as a general rule been less promising, perhaps because of the unacceptable toxicity associated with high systemic doses of IL-2. This has led to the suggestion that there is need to develop novel means of administering IL-2. J. E. Kolitz, et al., Interleukin-2: A Review, Arzenim.-Forsch. 35: 1607-15 (1985).
Interleukin-2 has recenty been tested in vivo in patients with malignant glioma. The IL-2 was administered through intracerebral injection. This administration route appears to avoid the toxicity effects associated with systemic administration of IL-2. Dosage levels of 10.sup.4 to 10.sup.6 U were well tolerated. S. K. Jacobs, et al., Interleukin-2 and Autologous Lymphokine-Killer Cells in the Treatment of Malignant Glioma, J. Neurosurg. 64: 743-749 (May 1986). However, for obvious reasons, intracerebral injection is not well sited for long-term therapy. Moreover, with any injection technique, available levels of the injected substance will fluctuate dramatically. This is particularly so in the case of IL-2, which has a half-life of less than thirty minutes in vivo. See J. E. Kolitz, et al., Interleukin-2: A Review, supra.
As a general rule, the brain is intolerant of foreign implants. Swelling or scarring of the brain is to be avoided if at all possible. Implants that enlarge the size of the brain are not feasible. At the same time, however, it is desirable that the brain be maintained in its normal anatomical dimension following neurosurgery involving tissue resection.
One of the serious problems attendant to neurosurgery, particularly neurosurgery that includes a craniotomy procedure, is hemorrhage. Hemostasis is a critical part of any surgical procedure involving the brain. This is of particular significance in malignant gliomas, which are believed to secrete hemolytic factors, resulting in complications such as post-operative intracerebral hemorrhage.
Accordingly, an object of the present invention is to provide a method and material for administering controlled doses of IL-2 to a patient over long periods of time with little maintenance.
Another object of the present invention is to provide a structurally compatible material and method for maintaining the brain in its normal anatomical dimension following removal of brain material.
It is yet a further object of the present invention to provide a material and method for promoting hemostasis following neurosurgery or other surgery.
Yet another object of the present invention is to provide a material and method for administering IL-2 locally, while avoiding systemic administration and toxicity.
Other objects, features, and advantages of the present invention will become apparent from the description of the invention which follows.